EP0425505B1 - Transdermate magensafthemmende wirkstoffe zur behandlung von magen-darm-erkrankungen - Google Patents

Transdermate magensafthemmende wirkstoffe zur behandlung von magen-darm-erkrankungen Download PDF

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Publication number
EP0425505B1
EP0425505B1 EP89906267A EP89906267A EP0425505B1 EP 0425505 B1 EP0425505 B1 EP 0425505B1 EP 89906267 A EP89906267 A EP 89906267A EP 89906267 A EP89906267 A EP 89906267A EP 0425505 B1 EP0425505 B1 EP 0425505B1
Authority
EP
European Patent Office
Prior art keywords
compound
transdermal
patch
composition
sulfinyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP89906267A
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English (en)
French (fr)
Other versions
EP0425505A1 (de
Inventor
Mary J. Ruwart
Wha Bin Im
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Pharmacia and Upjohn Co
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Upjohn Co
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Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Priority to AT89906267T priority Critical patent/ATE86857T1/de
Publication of EP0425505A1 publication Critical patent/EP0425505A1/de
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Publication of EP0425505B1 publication Critical patent/EP0425505B1/de
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to the treatment of gastrointestinal disease through a transdermally-administered anti-secretory agent.
  • gastric acid secretion is by the inhibition of gastric acid secretion.
  • gastric acid secretion can result in erosion of the epithelial cells, with consequent inflammation and ulceration.
  • Prevention and healing of such untoward gastric acid-induced effects can be achieved by the administration of a pharmacological agent which effectively inhibits gastric acid secretion.
  • Another important aspect to the prevention or treatment of gastrointestinal disease is the continuous, rather than intermittent, inhibition of gastric acid. It is therefore desirable to administer the drugs in a slow continuous fashion, over a long period of time, such that excess gastric acid secretion is minimised, to prevent gastrointestinal disease. Another important consideration is ease of administration and comfort.
  • EP-A-0150586 discloses that a continuous inhibition of acid can be achieved by administering a single dose of these compounds subcutaneously.
  • Subcutaneous administration of this class of compounds has been the only choice when a long duration of action (several days or weeks) is desired for a single dose.
  • severe days or weeks severe days or weeks
  • subcutaneous injection is not comfortable and sometimes can cause irritation to the surrounding tissue.
  • removal is difficult.
  • the present invention involves the use of a compound of formula I wherein X is S or SO; R1 is H, CH3, OCH3 or CF3; R2 is OCH3 or SR5 wherein R5 is (C1-C4)alkyl, (C2-C4)alkenyl, PhX, -CH2PhX or (C3-C10)cycloalkyl, wherein PhX is phenyl substituted by zero to 3 substituents selected from (C1-C4)alkyl, Cl, F, Br, NO2, CF3, OH and (C1 -C4) alkoxy; and R3 and R4 are the same or different and are each H or (C1-C4)alkyl.
  • the compound is first dissolved in a transdermal cream, paste, gel or liquid or otherwise absorbed into a transdermal patch.
  • a transdermal patch preferably comprises 1 to 300 mg of the compound.
  • the dissolved compound can then be applied to the skin of a mammal, preferably a human being, to be absorbed through the skin such that the (H+-K+) ATPase enzyme responsible for gastric acid secretion is inhibited.
  • a preferred compound from this family is 2-(4-ethylthio-3-methylpyridin -2-yl methyl)sulfinyl-benzimidazole and omeprazole which is when X is -S ⁇ O, R1 and R2 are methoxy and R3 and R4 are methyl.
  • transdermal vehicle such as a cream, gel, paste or liquid which are generally known in the art for transdermal use.
  • Typical transdermal compounds are polyethylene glycol, propylene glycol, triacetin, propylcarbonate, ethanol and isopropyl myristate.
  • the compounds can also be applied to porous or other material suitable for preparing a transdermal patch which can be worn by the patient.
  • transdermal vehicles are generally well-known in the pharmaceutical industry and therefore will not be discussed in detail.
  • the compounds are transdermally applied in a therapeutically effective amount to inhibit gastric acid secretion.
  • the amount is from 1 to 300 mg/dosage, preferably 100 to 200 mg/dosage.
  • the amount used in the transdermal vehicle is greatly in excess of the amount actually transferred into the body.
  • a typical cross-over rate is generally much less than the available drug present in the transdermal vehicle. The dosage is of course dependent upon the patient and diagnosed condition.
  • the subject compounds were dissolved in dimethyl sulfoxide (DMSO) and applied to the backs of rats and onto the ears of rabbits.
  • DMSO dimethyl sulfoxide
  • the animals were allowed to rest for varying amounts of time and then the inhibition of (H+-K+) ATPase, the enzyme responsible for gastric acid secretion, was measured.
  • mucosa from the fundic region was removed by blunt dissection and minced with scissors. 2.5 g of the minced tissue was placed in 25 ml of buffer containing 250 mM sucrose, 2 mM MgCl2, 1 mM EGTA, and 2mM Hepes/Tris, pH 7.4. The tissues were then prepared as described for the rat gastric mucosa.
  • Transdermal treatment with the subject compound reduced (H+-K+) ATPase activity 60-65% from control. Activity did not change with time.
  • the rats were prepared as described in Example 1 and fasted overnight. The same compound as in Example 1 was applied at 0, 100 or 200 mg/kg. Additional volumes (100 ⁇ l) of DMSO were spread over the treatment area one time (after two hours) or four times (after one, two, three and four hours). The animals were evaluated 5 hours after the initial dose for determination of (H+-K+) ATPase activity.
  • transdermal treatment 100 mg/kg reduced (H+-K+) ATpase activity 65% from control.
  • Additional applications of DMSO (four wipes) reduced the activity of the same dose an additional 16%.
  • a 200 mg/kg dose with one wipe of DMSO after two hours reduced the (H+-K+) ATpase activity by 72%.
  • the additional applications of DMSO were more effective (81%) than a single application at twice the dosage (200 mg/kg).
  • Rats were prepared as described in Example 1 and fasted overnight. The same compound as used in Example 1 was applied at 0, 25, 50, or 100 mg/kg. Additional volumes (100 ⁇ l) of DMSO were spread over the treatment area after 2, 5, and 7 hours. The animals were evaluated 24 hours after the initial dose for determination of (H+-K+) ATPase activity.
  • Example 2 Male, New Zealand White rabbits were fasted overnight without water in their cages prior to treatment. The same compound as used in Example 1 was applied at 0 or 100 mg/kg in divided doses (1/2 to each ear) to naive rabbit ears. The rabbits received an additional application of DMSO to the treatment area after 1, 3, 5, 7, 24 and 25 hrs. The rabbits were evaluated 30 hrs after the initial dose for determination of (H+-K+) ATPase activity.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Dermatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Materials For Medical Uses (AREA)

Claims (10)

  1. Verwendung einer Verbindung der Formel I
    Figure imgb0003
     oder eines pharmazeutisch akzeptablen Salzes derselben, für die Herstellung eines Medikaments zur Verwendung bei der Verhinderung oder Behandlung von. Gastrointestinalerkrankungen durch transdermale Hemmung der Magensäuresekretion;
    worin bedeuten:
    X S oder SO;
    R₁ H, CH₃, OCH₃ oder CF₃;
    R₂ OCH₃ oder SR₅ mit R₅ gleich (C₁-C₄)-Alkyl, (C₂-C₄)-Alkenyl, PhX, -CH₂PhX oder (C₃-C₁₀)-Cycloalkyl, wobei PhX = durch 0 bis 3 Substituent(en), ausgewählt aus (C₁-C₄)-Alkyl, Cl, F, Br, NO₂, CF₃, OH und (C₁-C₄)-Alkoxy substituiertes Phenyl und
    R₃ und R₄ gleich oder verschieden sind, jeweils H oder (C₁-C₄)-Alkyl.
  2. Verwendung nach Anspruch 1, worin die Verbindung aus 2-[[(4-Ethylthio-3-methylpyridin-2-yl)-methyl]-sulfinyl]-1H-benzimidazol besteht.
  3. Verwendung nach Anspruch 1, worin die Verbindung aus Omeprazole, d.h. 2-[[(3,5-Dimethyl-4-methoxypyridin-2-yl)-methyl]-sulfinyl]-5-methoxy-1H-benzimidazol besteht.
  4. Verwendung nach einem der vorhergehenden Ansprüche, wobei das Madikament in Form eines transdermalen Lappens vorliegt und die Verbindung in einer Creme, Paste, einem Gel oder einer Flüssigkeit gelöst oder in sonstiger Weise in den Lappen absorbiert ist.
  5. Verwendung nach Anspruch 4, wobei die Verbindung in einer Menge von 1 - 300 mg pro Lappen gelöst ist.
  6. Arzneimittelzubereitung, umfassend eine Verbindung der Formel I gemäß Anspruch 1 oder ein pharmazeutisch akzeptables Salz derselben und ein transdermales Vehikel.
  7. Zubereitung nach Anspruch 6, worin die Verbindung aus 2-[[(4-Ethylthio-3-methylpyridin-2-yl)-methyl]-sulfinyl]-1H-benzimidazol besteht.
  8. Zubereitung nach Anspruch 6, worin die Verbindung aus Omeprazole besteht.
  9. Zubereitung nach einem der Ansprüche 6 bis 8 in Form eines transdermalen Lappens, wobei die Verbindung in einer Creme, einer Paste, einem Gel oder einer Flüssigkeit gelöst oder in sonstiger Weise in den Lappen absorbiert ist.
  10. Zubereitung nach Anspruch 9, umfassend 1 - 300 mg der Verbindung pro Lappen.
EP89906267A 1988-06-30 1989-05-01 Transdermate magensafthemmende wirkstoffe zur behandlung von magen-darm-erkrankungen Expired - Lifetime EP0425505B1 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT89906267T ATE86857T1 (de) 1988-06-30 1989-05-01 Transdermate magensafthemmende wirkstoffe zur behandlung von magen-darm-erkrankungen.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21378688A 1988-06-30 1988-06-30
US213786 1988-06-30

Publications (2)

Publication Number Publication Date
EP0425505A1 EP0425505A1 (de) 1991-05-08
EP0425505B1 true EP0425505B1 (de) 1993-03-17

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Family Applications (1)

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EP89906267A Expired - Lifetime EP0425505B1 (de) 1988-06-30 1989-05-01 Transdermate magensafthemmende wirkstoffe zur behandlung von magen-darm-erkrankungen

Country Status (6)

Country Link
US (1) US5124158A (de)
EP (1) EP0425505B1 (de)
JP (1) JPH03505450A (de)
AU (1) AU3683889A (de)
CA (1) CA1324758C (de)
WO (1) WO1990000054A1 (de)

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PT698393E (pt) * 1993-05-19 2002-10-31 Hisamitsu Pharmaceutical Co Agente de solubilizacao e preparacao para uso externo contendo o mesmo
US5333621A (en) * 1993-05-28 1994-08-02 Eric Denzer Condom with transdermal vasodilator
US6007836A (en) * 1993-05-28 1999-12-28 Vericade, Inc. Transdermal vasodilator
US5708017A (en) * 1995-04-04 1998-01-13 Merck & Co., Inc. Stable, ready-to-use pharmaceutical paste composition containing proton pump inhibitors
US6699885B2 (en) * 1996-01-04 2004-03-02 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and methods of using same
US6645988B2 (en) 1996-01-04 2003-11-11 Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US5840737A (en) 1996-01-04 1998-11-24 The Curators Of The University Of Missouri Omeprazole solution and method for using same
US6489346B1 (en) 1996-01-04 2002-12-03 The Curators Of The University Of Missouri Substituted benzimidazole dosage forms and method of using same
US6096340A (en) * 1997-11-14 2000-08-01 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6174548B1 (en) 1998-08-28 2001-01-16 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6733778B1 (en) 1999-08-27 2004-05-11 Andrx Pharmaceuticals, Inc. Omeprazole formulation
US6312723B1 (en) 1999-08-26 2001-11-06 Robert R. Whittle Pharmaceutical unit dosage form
US6262085B1 (en) 1999-08-26 2001-07-17 Robert R. Whittle Alkoxy substituted Benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6326384B1 (en) 1999-08-26 2001-12-04 Robert R. Whittle Dry blend pharmaceutical unit dosage form
US6262086B1 (en) 1999-08-26 2001-07-17 Robert R. Whittle Pharmaceutical unit dosage form
US6268385B1 (en) 1999-08-26 2001-07-31 Robert R. Whittle Dry blend pharmaceutical formulations
US6369087B1 (en) 1999-08-26 2002-04-09 Robert R. Whittle Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same
US6312712B1 (en) 1999-08-26 2001-11-06 Robert R. Whittle Method of improving bioavailability
US6780880B1 (en) * 1999-08-26 2004-08-24 Robert R. Whittle FT-Raman spectroscopic measurement
US6316020B1 (en) 1999-08-26 2001-11-13 Robert R. Whittle Pharmaceutical formulations
AU2001296908A1 (en) * 2000-09-29 2002-04-08 Geneva Pharmaceuticals, Inc. Proton pump inhibitor formulation
US20040006111A1 (en) * 2002-01-25 2004-01-08 Kenneth Widder Transmucosal delivery of proton pump inhibitors
US20030228363A1 (en) * 2002-06-07 2003-12-11 Patel Mahendra R. Stabilized pharmaceutical compositons containing benzimidazole compounds
US20040106713A1 (en) * 2002-12-03 2004-06-03 Avakian Roger W. Use of additives in compounds containing macrocyclic poly(alkylene dicarboxylate) oligomers
EP1603537A4 (de) * 2003-02-20 2009-11-04 Santarus Inc Neuartige formulierung, antazidkomplex-immediatfreisetzung für eine schnelle und anhaltende unterdrückung von magensäure
JP2006528182A (ja) * 2003-07-18 2006-12-14 サンタラス インコーポレイティッド 薬学的製剤および酸に起因する消化器疾患の治療法
US8993599B2 (en) * 2003-07-18 2015-03-31 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US7419996B2 (en) * 2003-08-13 2008-09-02 The University Of Houston Parenteral and oral formulations of benzimidazoles
US20070292498A1 (en) * 2003-11-05 2007-12-20 Warren Hall Combinations of proton pump inhibitors, sleep aids, buffers and pain relievers
US20080287502A1 (en) * 2004-03-30 2008-11-20 Dermatrends, Inc. Transdermal Administration of Proton Pump Inhibitors
US8906940B2 (en) * 2004-05-25 2014-12-09 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US8815916B2 (en) * 2004-05-25 2014-08-26 Santarus, Inc. Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them
US20090092658A1 (en) * 2007-10-05 2009-04-09 Santarus, Inc. Novel formulations of proton pump inhibitors and methods of using these formulations

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SE7804231L (sv) * 1978-04-14 1979-10-15 Haessle Ab Magsyrasekretionsmedel
US4575554A (en) * 1983-12-05 1986-03-11 The Upjohn Company Substituted 2-pyridylmethylthio- and sulfinyl-benzimidazoles as gastric antisecretory agents
US4743588A (en) * 1984-06-13 1988-05-10 Allergan Pharmaceuticals, Inc. Compositions and methods of enhancing transdermal and transmembrane penetration systemic agents
IE58373B1 (en) * 1986-06-18 1993-09-08 Bloomfield Frederick Jacob 5-Lipoxygenase pathway inhibitors
AU607172B2 (en) * 1986-12-22 1991-02-28 Cygnus, Inc. Diffusion matrix for transdermal drug administration
US4915950A (en) * 1988-02-12 1990-04-10 Cygnus Research Corporation Printed transdermal drug delivery device

Also Published As

Publication number Publication date
EP0425505A1 (de) 1991-05-08
WO1990000054A1 (en) 1990-01-11
AU3683889A (en) 1990-01-23
CA1324758C (en) 1993-11-30
JPH03505450A (ja) 1991-11-28
US5124158A (en) 1992-06-23

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